Aneurysmal disease of the aorta is a common cause of death in the United States. Thoracic aortic aneurysm (TAA) patients are particularly challenging because of the complexity of surgical repair and high incidence of postoperative morbidity. Aortic aneurysms represent a vascular remodeling process characterized by loss of the aortic medial layer caused, at least in part, by degradation of the extracellular matrix (ECM). The overall goal of this project is to define the extracellular mechanisms contributing to the progression of TAA. The matrix metalloproteinases (MMPs) degrade the ECM both in health and disease. MMPs and their tissue inhibitors (TIMPs) are produced by many cell types including those found in the aorta. Past clinical studies have suggested an imbalance occurs between MMPs and TIMPs in resected aortic aneurysms. The central hypotheses of this project are that alterations in MMP/TIMP stoichiometry is an early event in TAA progression; that targeted modulation of MMP/TIMP stoichiometry will directly modify TAA progression; and that a fundamental cellular mechanism for TAA progression is regional alterations in fibroblast MMP/TIMP expression. Using a murine model of TAA developed in this laboratory, this project will accomplish the following aims: (1) Establish the temporal-spatial relationship of TAA progression to local MMP/TIMP levels; (2) Modify the natural history of TAA through targeted MMP-9 gene deletion (MMP loss of function) or TIMP- 1 gene deletion (MMP gain of function); (3) Establish that MMP-9 gene induction is an early event in TAA progression and that a fundamental cell type responsible for abnormal MMP/TIMP expression is the fibroblast. The outcomes from this project will establish mechanistic insight into the formation and progression of thoracic aneurysms and provide the basis for rational designs for therapeutic modulation in patients with this devastating disease.